Spinal cord injury (SCI) is a devastating event that constitutes a major health issue. At the present time, no effective treatments exist for the treatment of SCI and strategies that promote functional recovery are clearly warranted. The objective of this UOI proposal is to conduct IND-enabling preclinical studies for the use of NIM811, an inhibitor of mitochondrial permeability transition (mPT), in the treatment of acute SCI. This approach is based on the underlying hypothesis that maintaining mitochondrial function, a critical process for limiting ongoing cell death and dysfunction, will enhance recovery of function following SCI. Current experimental studies and clinical observations suggest that the cyclosporin A (CsA), which inhibits mPT and promotes mitochondrial stability, can be of therapeutic benefit in the treatment of acute traumatic brain injury, spinal cord injury, and more recently in reperfusion injury following acute myocardial infarction. However, CsA has a high toxicity profile and its immunosuppressive properties make it difficult to attribute any neuroprotective effects on inhibition of mPT. Therefore, compounds that mimic the cytoprotective actions of CsA on mPT, but exhibit minimal immunosuppressive properties and lower cytotoxicity have high therapeutic potential. NIM811 (Novartis) is a non-immunosuppressive cyclosporin analog that inhibits mPT at nanomolar concentrations and exhibits a significantly lower toxicity profile. Substantial "proof-of-concept" studies from this lab have demonstrated in vivo efficacy of NIM811 on a number of functional outcomes using an experimental rat model of moderate SCI. The experimental plan will expand on these previous observations by documenting NIM811 functional efficacy in models of moderate and severe SCI using a repeated dosing paradigm (Specific Aim 1). Pharmacokinetic studies and assays of mitochondrial function will be used to identify a clinically relevant therapeutic time window (Specific Aim 2). Long-term functional studies will then be performed using the most effective repeated dose and optimal therapeutic window (Specific Aim 3). A pre-IND meeting will then be held with the FDA to identify and conduct, if necessary, any additional IND- enabling toxicity studies (Specific Aim 4). The completion of these Aims will culminate in the filing of an IND application in order to initiate a Phase I human clinical trial. RELEVANCE: Spinal cord injury (SCI) is a devastating event that constitutes a major health issue. In the United States alone, approximately 12,000 new cases occur each year and some 250,000 people are currently living with SCI. The lifetime health care-related costs per individual are estimated to be around $1,000,000. At the present time, no effective treatments exist for the treatment of SCI. These experimental studies will focus on testing a highly promising drug designed to promote recovery using an early intervention approach.